LUIZA GUILHERME GUGLIELMI

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Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina
LIM/19 - Laboratório de Histocompatibilidade e Imunidade Celular, Hospital das Clínicas, Faculdade de Medicina - Líder

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  • article 24 Citação(ões) na Scopus
    Anti-Group A Streptococcal Vaccine Epitope STRUCTURE, STABILITY, AND ITS ABILITY TO INTERACT WITH HLA CLASS II MOLECULES
    (2011) GUILHERME, Luiza; ALBA, Martha P.; FERREIRA, Frederico Moraes; OSHIRO, Sandra Emiko; HIGA, Fabio; PATARROYO, Manuel E.; KALIL, Jorge
    Streptococcus pyogenes infections remain a health problem in several countries due to poststreptococcal sequelae. We developed a vaccine epitope (StreptInCor) composed of 55 amino acids residues of the C-terminal portion of the M protein that encompasses both T and B cell protective epitopes. The nuclear magnetic resonance (NMR) structure of the StreptInCor peptide showed that the structure was composed of two microdomains linked by an 18-residue alpha-helix. A chemical stability study of the StreptInCor folding/unfolding process using far-UV circular dichroism showed that the structure was chemically stable with respect to pH and the concentration of urea. The T cell epitope is located in the first microdomain and encompasses 11 out of the 18 alpha-helix residues, whereas the B cell epitope is in the second microdomain and showed no alpha-helical structure. The prediction of StreptInCor epitope binding to different HLA class II molecules was evaluated based on an analysis of the 55 residues and the theoretical possibilities for the processed peptides to fit into the P1, P4, P6, and P9 pockets in the groove of several HLA class II molecules. We observed 7 potential sites along the amino acid sequence of StreptInCor that were capable of recognizing HLA class II molecules (DRB1*, DRB3*, DRB4*, and DRB5*). StreptInCoroverlapping peptides induced cellular and humoral immune responses of individuals bearing different HLA class II molecules and could be considered as a universal vaccine epitope.
  • article 47 Citação(ões) na Scopus
    RHEUMATIC HEART DISEASE: MEDIATION BY COMPLEX IMMUNE EVENTS
    (2011) GUILHERME, L.; KOEHLER, K. F.; KALIL, J.
    Rheumatic fever (RF) is an autoimmune disease caused by the Gram-positive bacteria Streptococcus pyogenes following an untreated throat infection in susceptible children. Rheumatic heart disease (RHD), the most serious complication, occurs in 30-45% of RF patients and leads to chronic valvular lesions. Here, we focus on the genes that confer susceptibility for developing this disease. Molecular mimicry mediates the cross-reactions between streptococcal antigens and human proteins. Several autoantigens have been identified, including cardiac myosin epitopes, vimentin, and other intracellular proteins. In heart tissue, antigen-driven oligoclonal T cell expansions probably cause the rheumatic heart lesions. These cells are CD4(+) and produce inflammatory cytokines (TNF alpha and IFN gamma). IL-4(+) cells are found in the myocardium; however, these cells are very scarce in the valve lesions of RHD patients. IL-4 is a Th2-type cytokine and plays a regulatory role in the inflammatory response mediated by Th1 cytokines. Our findings indicate that the Th1/Th2 cytokine balance has a role in healing myocarditis while the low numbers of IL-4-producing cells in the valves probably induced the progressive and permanent valve damage.
  • article 32 Citação(ões) na Scopus
    CXCL9/Mig Mediates T cells Recruitment to Valvular Tissue Lesions of Chronic Rheumatic Heart Disease Patients
    (2013) FAE, Kellen C.; PALACIOS, Selma A.; NOGUEIRA, Luciana G.; OSHIRO, Sandra E.; DEMARCHI, Lea M. F.; BILATE, Angelina M. B.; POMERANTZEFF, Pablo M. A.; BRANDAO, Carlos; THOMAZ, Petronio G.; REIS, Maxwell dos; SAMPAIO, Roney; TANAKA, Ana C.; CUNHA-NETO, Edecio; KALIL, Jorge; GUILHERME, Luiza
    Rheumatic fever (RF) is an autoimmune disease triggered by Streptococcus pyogenes infection frequently observed in infants from developing countries. Rheumatic heart disease (RHD), the major sequel of RF, leads to chronic inflammation of the myocardium and valvular tissue. T cells are the main population infiltrating cardiac lesions; however, the chemokines that orchestrate their recruitment are not clearly defined. Here, we investigated the expression of chemokines and chemokine receptors in cardiac tissue biopsies obtained from chronic RHD patients. Our results showed that CCL3/MIP1 alpha gene expression was upregulated in myocardium while CCL1/I-309 and CXCL9/Mig were highly expressed in valvular tissue. Auto-reactive T cells that infiltrate valvular lesions presented a memory phenotype (CD4(+)CD45RO(+)) and migrate mainly toward CXCL9/Mig gradient. Collectively, our results show that a diverse milieu of chemokines is expressed in myocardium and valvular tissue lesions and emphasize the role of CXCL9/Mig in mediating T cell recruitment to the site of inflammation in the heart.
  • bookPart 2 Citação(ões) na Scopus
    Rheumatic Fever: How Streptococcal Throat Infection Triggers an Autoimmune Disease
    (2015) GUILHERME, L.; KALIL, J.
    Molecular mimicry between streptococcal and human proteins has been proposed as the triggering factor leading to autoimmunity in rheumatic fever (RF) and rheumatic heart disease (RHD). Punctual genetic polymorphisms related to both innate and adaptive immune responses are involved in the development of RF/RHD. Some adhesion molecules and chemokines facilitate the monocytes and macrophages and T and B cell infiltration to the heart-tissue. Here we presented data on molecular mimicry mediated by B and T cell responses of peripheral blood and T cell clones infiltrating heart lesions from RHD patients against streptococcal antigens and human tissue proteins. The molecular analysis of T cell recognition is assessed by the definition of heart-cross reactive antigens. Degenerate patterns of T cell receptor (TCR) recognition in which intralesional T cell clones presenting the same TCR-BVJB and AVJB and recognized different antigens are described. The production of inflammatory cytokines such as TNFa, IL-2, IL-17, IL-23 and IFNg from peripheral and heart-infiltrating mononuclear cells, suggested that Th-1 and Th-17 type cytokines are the mediators of RHD heart lesions. All the results presented here delineate the mechanisms involved in RF/RHD and can certainly be a model for other autoimmune diseases. © 2015 Elsevier B.V. All rights reserved.
  • conferenceObject
    RESTRICTED AND SKEWED TCR VB REPERTOIRE IN CHROMOSOME 22Q11.2 DELETION
    (2012) ARANTES, J. M.; GRASSI, M. S.; SANTOS, N. M.; GUILHERME, L.; KULIKOWSKI, L. D.; DUTRA, R. L.; WATANABE, L. A.; JACOB, C. M. A.; ZAGO, C. A.; CARNEIRO-SAMPAIO, M.
    Introduction: Chromosome 22q11 deletion is the most common human deletion and is found in the majority of patients with DiGeorge and velo-cardio-facial syndromes. Many patients have a mild to moderate immunodeficiency, and most have cardiac anomaly. Objective: To evaluate TCR repertoire diversity in infants with 22q11.2 deletion identified at FMUSP ward for congenital heart diseases. Methods: TCR Vβ variable chain repertoire was analyzed by the TCRBV CDR3 lenght spectratyping technique, and repertoire diversity was quantified utilizing the complexity score (CS), that represents the sum of the number of peaks for each one of the 24 BV families. 22q11.2 deletion was detected utilizing multiplex ligation-dependent probe amplification. First case report: A 9-month-old boy was identified in a survey among infants with complex congenital heart anomalies. He was born from non-consanguineous parents, weighing 2845g and presenting microcephaly, micrognathia, ocular hypertelorism and low set left ear, renal involvement, left atrial isomerism and pulmonary atresia. He also had hypocalcemia and hypoplasticthymus. He has lymphopenia=3,800 cells/mm3 (CD3=1,454 cells/mm3, CD4=888cells/mm3, CD8=537cells/mm3), thrombocytopenia=55,000, IgG+=1,285mg/dL, IgM=123mg/dL, IgA=132mg/dL. Results: The patient presented CS=49, in contrast with 2 healthy age-matched male infants with 127 and 135. Four young healthy adults presented CS between 165 and 178. The patient presented mostly olygoclonal distribution and even absence of TCRBV families, while healthy donors exhibited mainly polyclonal non-Gaussian distributions. Conclusions: The evaluation of new cases as well as the follow-up the patients will demonstrate if the repertoire diversity correlates with clinical severity.
  • article 17 Citação(ões) na Scopus
    A Vaccine against Streptococcus pyogenes The Potential to Prevent Rheumatic Fever and Rheumatic Heart Disease
    (2013) GUILHERME, Luiza; FERREIRA, Frederico Moraes; KOEHLER, Karen Francine; POSTOL, Edilberto; KALIL, Jorge
    Streptococcus pyogenes causes severe, invasive infections such as the sequelae associated with acute rheumatic fever, rheumatic heart disease, acute glomerulonephritis, uncomplicated pharyngitis, and pyoderma. Efforts to produce a vaccine against S. pyogenes began several decades ago, and different models have been proposed. We have developed a vaccine candidate peptide, StreptInCor, comprising 55 amino acid residues of the C-terminal portion of the M protein and encompassing both the T- and B-cell protective epitopes. The present article summarizes data from the previous 5 years during which we tested the immunogenicity and safety of StreptInCor in different animal models. We showed that StreptInCor overlapping peptides induced cellular and humoral immune responses of individuals bearing different HLA class II molecules. These results are consistent with peptides that have a universal vaccine epitope. The tridimensional molecular structure of StreptInCor was elucidated by nuclear magnetic resonance spectroscopy, which showed that its structure is composed of two microdomains linked by an 18-residue alpha-helix. Additionally, we comprehensively evaluated the structural stability of the StreptInCor peptide in different physicochemical conditions using circular dichroism. Additional experiments were performed with inbred, outbred, and HLA class II transgenic mice. Analysis of several organs of these mice showed neither deleterious nor autoimmune reactions even after a long period of vaccination, indicating that the StreptInCor candidate peptide could be considered as an immunogenic and safe vaccine.
  • article 29 Citação(ões) na Scopus
    HLA class II transgenic mice develop a safe and long lasting immune response against StreptInCor, an anti-group A streptococcus vaccine candidate
    (2011) GUERINO, Milton T.; POSTOL, Edilberto; DEMARCHI, Lea M. F.; MARTINS, Carlo O.; MUNDEL, Luiz R.; KALIL, Jorge; GUILHERME, Luiza
    Streptococcus pyogenes infections remain a health problem in several countries because of post-streptococcal sequelae, such as rheumatic fever and rheumatic heart disease. We developed a vaccine epitope (StreptInCor) composed of 55 amino acid residues of the C-terminal portion of the M protein that encompasses both T and B cell protective epitopes. Recently, by using human blood samples, we showed that the StreptInCor epitope is able to bind to different HLA class 11 molecules and that it could be considered a universal vaccine epitope. In the present work, we evaluated the immune response of HLA class II transgenic mice against aluminum hydroxide-absorbed StreptInCor. After a period of one year, several organs were analyzed histologically to verify the safety of the candidate vaccine epitope. Our results showed that StreptInCor is able to induce robust and safe and long lasting immune response without deleterious reactions in several organs. In conclusion, the results presented here indicate that StreptInCor could be considered a safe vaccine against severe streptococcus-induced diseases.
  • article 368 Citação(ões) na Scopus
    Acute rheumatic fever and rheumatic heart disease
    (2016) CARAPETIS, Jonathan R.; BEATON, Andrea; CUNNINGHAM, Madeleine W.; GUILHERME, Luiza; KARTHIKEYAN, Canesan; MAYOSI, Bongani M.; SABLE, Craig; STEER, Andrew; WILSON, Nigel; WYBER, Rosemary; ZUHLKE, Lies
    Acute rheumatic fever (ARE) is the result of an autoimmune response to pharyngitis caused by infection with group A Streptococcus. The long-term damage to cardiac valves caused by ARF, which can result from a single severe episode or from multiple recurrent episodes of the illness, is known as rheumatic heart disease (RHD) and is a notable cause of morbidity and mortality in resource-poor settings around the world. Although our understanding of disease pathogenesis has advanced in recent years, this has not led to dramatic improvements in diagnostic approaches, which are still reliant on clinical features using the Jones Criteria, or treatment practices. Indeed, penicillin has been the mainstay of treatment for decades and there is no other treatment that has been proven to alter the Likelihood or the severity of RHD after an episode of ARE. Recent advances including the use of echocardiographic diagnosis in those with ARF and in screening for early detection of RHD, progress in developing group A streptococcal vaccines and an increased focus on the Lived experience of those with RHD and the need to improve quality of life give cause for optimism that progress will be made in coming years against this neglected disease that affects populations around the world, but is a particular issue for those Living in poverty.
  • article 9 Citação(ões) na Scopus
    Rheumatic Heart Disease: Pathogenesis and Vaccine
    (2018) GUILHERME, L.; BARROS, S. Freschi de; KOHLER, K. F.; SANTOS, S. R.; FERREIRA, F. Morais; SILVA, W. R.; ALENCAR, R.; POSTOL, E.; KALIL, J.
    Rheumatic fever (RF) and rheumatic heart disease (RHD) follow untreated S. pyogenes throat infections in children who present susceptible genes that favor the development of autoimmune reactions. In this review, we focus on the genes that confer susceptibility and on the autoimmune reactions that occur due to molecular mimicry between human-tissue proteins and streptococcal M protein. Polyarthritis is the initial manifestation, which can evolve to carditis and severe valve damage; these culminate in rheumatic heart disease (RHD) or Sydenham's chorea, which affects the central nervous system. A perspective on vaccine development to prevent the disease is also discussed.
  • article 29 Citação(ões) na Scopus
    Analysis of the coverage capacity of the StreptInCor candidate vaccine against Streptococcus pyogenes
    (2014) AMICIS, Karine M. De; BARROS, Samar Freschi de; ALENCAR, Raquel E.; POSTOL, Edilberto; MARTINS, Carlo de Oliveira; ARCURI, Helen Andrade; GOULART, Cibelly; KALIL, Jorge; GUILHERME, Luiza
    Streptococcus pyogenes is responsible for infections as pharyngitis, sepsis, necrotizing fasciitis and streptococcal toxic shock syndrome. The M protein is the major bacterial antigen and consists of both polymorphic N-terminal portion and a conserved region. In the present study, we analyzed the in vitro ability of StreptInCor a C-terminal candidate vaccine against S. pyogenes to induce antibodies to neutralize/opsonize the most common S. pyogenes strains in Sao Paulo by examining the recognition by sera from StreptInCor immunized mice. We also evaluated the presence of cross-reactive antibodies against human heart valve tissue. Anti-StreptInCor antibodies were able to neutralize/opsonize at least 5 strains, showing that immunization with StreptInCor is effective against several S. pyogenes strains and can prevent infection and subsequent sequelae without causing autoimmune reactions.